Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell.,Nature Metabolism

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Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell.
Nature Metabolism ( IF 18.9 ) Pub Date : 2019-11-15 , DOI: 10.1038/s42255-019-0135-7
Danusa Menegaz ₁ , D Walker Hagan ₂ , Joana Almaça ₁ , Chiara Cianciaruso ₃ , Rayner Rodriguez-Diaz ₁ , Judith Molina ₁ , Robert M Dolan ₂ , Matthew W Becker ₂ , Petra C Schwalie _{3,

4} , Rita Nano ₅ , Fanny Lebreton ₆ , Chen Kang _{7,

8} , Rajan Sah _{7,

8} , Herbert Y Gaisano ₉ , Per-Olof Berggren _{10,

11,

12} , Steinunn Baekkeskov _{3,

13} , Alejandro Caicedo _{1,

10,

14,

15} , Edward A Phelps _{2,

3}

Affiliation

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA.
Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Pancreatic Islet Processing Facility, Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Cell Isolation and Transplantation Center, Faculty of Medicine, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
Center for Cardiovascular Research and Division of Cardiology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA.
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, USA.
Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
The Rolf Luft Research Center for Diabetes & Endocrinology, Karolinska Institutet, Stockholm, Sweden.
Division of Integrative Biosciences and Biotechnology, WCU Program, University of Science and Technology, Pohang, Korea.
Departments of Medicine and Microbiology/Immunology, Diabetes Center, University of California San Francisco, San Francisco, CA, USA.
Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL, USA.
Program in Neuroscience, Miller School of Medicine, University of Miami, Miami, FL, USA.

Pancreatic beta cells synthesize and secrete the neurotransmitter γ-aminobutyric acid (GABA) as a paracrine and autocrine signal to help regulate hormone secretion and islet homeostasis. Islet GABA release has classically been described as a secretory vesicle-mediated event. Yet, a limitation of the hypothesized vesicular GABA release from islets is the lack of expression of a vesicular GABA transporter in beta cells. Consequentially, GABA accumulates in the cytosol. Here we provide evidence that the human beta cell effluxes GABA from a cytosolic pool in a pulsatile manner, imposing a synchronizing rhythm on pulsatile insulin secretion. The volume regulatory anion channel (VRAC), functionally encoded by LRRC8A or Swell1, is critical for pulsatile GABA secretion. GABA content in beta cells is depleted and secretion is disrupted in islets from type 1 and type 2 diabetic patients, suggesting that loss of GABA as a synchronizing signal for hormone output may correlate with diabetes pathogenesis.

中文翻译：

人 β 细胞胞浆池脉冲式 GABA 分泌的机制和影响。

胰腺 β 细胞合成并分泌神经递质 γ-氨基丁酸 (GABA) 作为旁分泌和自分泌信号，帮助调节激素分泌和胰岛稳态。胰岛 GABA 释放传统上被描述为分泌囊泡介导的事件。然而，假设的胰岛囊泡 GABA 释放的局限性在于 β 细胞中缺乏囊泡 GABA 转运蛋白的表达。因此，GABA 在细胞质中积累。在这里，我们提供的证据表明，人类 β 细胞以脉冲方式从胞质池中流出 GABA，对脉冲胰岛素分泌施加同步节律。容量调节阴离子通道 (VRAC) 在功能上由 LRRC8A 或 Swell1 编码，对于脉冲式 GABA 分泌至关重要。 1 型和 2 型糖尿病患者的胰岛中，β 细胞中的 GABA 含量耗尽，分泌受到破坏，这表明作为激素输出同步信号的 GABA 丧失可能与糖尿病发病机制相关。

更新日期：2019-11-17

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